Successful Prediction of Human Fetal Exposure to P-Glycoprotein Substrate Drugs Using the Proteomics-Informed Relative Expression Factor Approach and PBPK Modeling and Simulation
Olena Anoshchenko, Flavia Storelli, Jashvant D. Unadkat
Abstract
Many women take drugs during their pregnancy to treat a variety of clinical conditions. To optimize drug efficacy and reduce fetal toxicity, it is important to determine or predict fetal drug exposure throughout pregnancy. Previously, we developed and verified a maternal-fetal physiologically based pharmacokinetic (m-f PBPK) model to predict fetal K<sub>p,uu</sub> (unbound fetal plasma AUC/unbound maternal plasma AUC) of drugs that passively cross the placenta. Here, we used in vitro transport studies in Transwell, in combination with our m-f PBPK model, to predict fetal K<sub>p,uu</sub> of drugs that are effluxed by placental P-glycoprotein (P-gp)—namely, dexamethasone, betamethasone, darunavir, and lopinavir. Using Transwell, we determined the efflux ratio of these drugs in hMDR1-MDCK<sup>cP-gpKO</sup> cells, in which human P-gp was overexpressed and the endogenous P-gp was knocked out. Then, using the proteomics-informed efflux ratio–relative expressive factor approach, we predicted the fetal K<sub>p,uu</sub> of these drugs at term. Finally, to verify our predictions, we compared them with the observed in vivo fetal K<sub>p,uu</sub> at term. The latter was estimated using our m-f PBPK model and published fetal [umbilical vein (UV)]/maternal plasma drug concentrations obtained at term (UV/maternal plasma). Fetal K<sub>p,uu</sub> predictions for dexamethasone (0.63), betamethasone (0.59), darunavir (0.17), and lopinavir (0.08) were successful, as they fell within the 90% confidence interval of the corresponding in vivo fetal K<sub>p,uu</sub> (0.30–0.66, 0.29–0.71, 0.11–0.22, 0.04–0.19, respectively). This is the first demonstration of successful prediction of fetal K<sub>p,uu</sub> of P-gp drug substrates from in vitro studies. <h3>SIGNIFICANCE STATEMENT</h3> For the first time, using in vitro studies in cells, this study successfully predicted human fetal K<sub>p,uu</sub> of P-gp substrate drugs. This success confirms that the m-f PBPK model, combined with the ER-REF approach, can successfully predict fetal drug exposure to P-gp substrates. This success provides increased confidence in the use of the ER-REF approach, combined with the m-f PBPK model, to predict fetal K<sub>p,uu</sub> of drugs (transported by P-gp or other transporters), both at term and at earlier gestational ages.